Rethinking Cell Therapy for Severe Limb Ischemia

Abstract

Severe Limb Ischemia (SLI) is the most advanced stage of peripheral arterial disease; patients present with ischemic pain or necrosis in the lower extremities. SLI has a poor prognosis for life and limb and ca. 20-40% of patients reach a point where surgical revascularization options are exhausted and amputation is indicated. Cell therapy using adult progenitor cells has been proposed as a new treatment option for these patients. In a prior clinical trial by our group (the JUVENTAS trial) we have shown that treatment with autologous bone marrow mono-nuclear cells (BM-MNCs) did not prevent major amputations in SLI patients, despite strong effects in pre-clinical studies. In the present work we explore possible reasons that may have lead to the negative trial result and try to identify an optimized treatment for future trials. Amongst other things we show that the amount of progentor cells in the bone marrow of SLI patients is depleted, which is associated with poor disease outcome and likely poor efficacy of autologous treatment. Furthermore we show that ex vivo expansion of a specific progenitor cell population, Mesenchymal Stromal Cells (MSCs), appears unaffected by disease processes. The thus obtained MSCs show a strong pro-angiogenic capacity, equivalent to MSCs obtained from healthy donors. We conclude with recommendations for a future clinical study using MSCs.